Placebo Treatment Research Articles

Treatment of Melasma with Tranexamic Acid Essence Combined with Iontophoresis: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

This randomized, double-blind, placebo-controlled trial aimed to evaluate the efficacy of tranexamic acid essence combined with iontophoresis in treating melasma. Thirty participants were recruited and randomly assigned to the experimental (Group A) or control group (Group B). Group A received tranexamic acid essence iontophoresis treatment twice weekly for three months, while Group B received placebo treatment. Melasma Area and Severity Index (MASI) scores and skin luminance (L) values were assessed at baseline and weeks 4, 8, and 12. No significant differences in baseline characteristics were observed between the groups. The mean MASI score reduction rate was significantly higher in Group A (-0.10±0.12%) compared to Group B (-0.02±0.09%) (p<0.05). Skin L values significantly increased in Group A from 61.32±3.53 to 63.32±1.78, while slightly decreasing in Group B (p=0.037). Tranexamic acid essence combined with iontophoresis significantly improved MASI scores and skin luminance compared to placebo, demonstrating its effectiveness in treating melasma. Further research with larger sample sizes and longer follow-up is warranted to validate long-term effects and recurrence rates.

Randomized placebo controlled trial of phytoterpenes in DMSO for the treatment of plantar fasciitis

Plantar fasciitis is the most common cause of heel pain in adults with an overall prevalence of 0.85% in the adult population of the US, affecting over 2 million adults annually. Most current treatment modalities are not supported by sufficient evidence to recommend one particular strategy over another. Topical application of analgesics for soft tissue pain is well established, however the plantar fascia presents challenges in this regard due to thick skin, fibrotic tissue, and an often thickened fat pad. Sixty-two patients with plantar fasciitis were randomized to a placebo controlled trial testing the efficacy of a topical solution of plant terpenes containing camphor, menthol, eugenol, eucalyptol, and vanillin. Skin permeation of the mixture was enhanced with 15% dimethylsulfoxide (DMSO), 1% limonene, and rosemary oil. One ml of solution was applied topically twice daily, and pain scores evaluated on Day 0, Day 1, Day 3, and Day 10. Using the validated foot function index 78.1% of patients reported an 85% or greater decrease in their total pain score by day 10 while placebo treatment was without effect (One Way ANOVA, P < 0.01). This study adapts the treatment modality of topical analgesia for soft tissue pain to a problematic area of the body and shows therapeutic promise.ClinicalTrials.gov Identifier: NCT05467631

SAFETY AND EFFICACY OF BEMPEDOIC ACID AS A MONO AND COMBINED THERAPY IN STATIN HYPERLIPIDEMIC PATIENT: A SYSTEMATIC REVIEW

Cardiovascular diseases (CVD) are the prominent cause of death both in the United States and worldwide. Hyperlipidemia is the primary risk factor that leads to atherosclerosis and several other vascular diseases. statin therapy has been the most prescribed therapy for hyperlipidemia for almost three decades, but the prescription comes with some adverse side effects. Bempedoic acid is a novel oral drug recently approved by the FDA for hyperlipidemia patients especially it is beneficial for those who are facing statin intolerance. The studies were collected from different databases i.e. PubMed, clinicaltrails.gov, web of Science, and Google Scholar. The selection criteria were based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. The phase 2 trials showed reducing Low-density lipoproteins (LDL) by 27% at a dosage of 120 mg of Bempedoic acid. When Bempedoic acid and ezetimibe are administered alone, LDL-C levels are reduced by 13-23% and 13-20%, respectively. Bempedoic acid+ atorvastatin causes a reduction of LDL to 22%, but with a placebo treatment, there will be no reduction in LDL level. Bempedoic acid 120 mg plus ezetimibe 10mg LDL-C levels decreased by 43% and 48% with Bempedoic acid 180 mg plus ezetimibe 10mg. Bempedoic acid has an interesting biochemical profile and presents an interesting new option for managing the complex dyslipidemia issue. The FDA has approved Bempedoic acid and Bempedoic acid plus antihyperlipidemic agents for the treatment of people with Heterozygous Familial Hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who need further LDL-C reduction with statin therapy that is maximally tolerable.

Rhodiola Rosea: a plant from the Crassulaceae family that has the potential to reduce muscle pain and increase range of motion during exercise-induced muscle damage

This study aims to analyze the potential of rhodiola rosea in reducing muscle pain and increasing ROM during EIMD. This experimental research uses a pre- and post-control group design. Research subjects were selected using a purposive sampling technique, then the subjects were divided into 2 groups, namely group (K1) which was given placebo and group (K2) which was given rhodiola rosea at a dose of 500 mg. A total of 18 healthy men aged between 19-25 years participated in this study. Data collection began on the first day by collecting data on subject characteristics. After that, they were asked to warm up. Physical activity is carried out afterward. These activities include high-intensity activities, such as walking lunges, good mornings, and leg extensions. This exercise is done in 4 sets with a 1-minute break (recovery) between sets. Exercise intensity is monitored using a Polar H9 Heart Rate Sensor. On day 2 or 24 hours after training, subjects took pre-test data to measure muscle soreness and ROM. Subjects were then given placebo or rhodiola rosea treatment, depending on the group assigned. On the 3rd day or 48 hours after training, post-test data was collected again. Muscle intensity was measured using a Visual Analog Scale (VAS) and ROM was measured at the knee joint using a goniometer. After the data was obtained, the data were analyzed using the IBM SPSS version 26 application. The results of this study reported that the K1 group given placebo did not significantly reduce muscle pain and increase ROM during EIMD, while the K2 group given rhodiola rosea at a dose of 500 mg significantly reduced pain. muscle and increase ROM during EIMD. Considering that pain management and ROM are very necessary to support body function, we recommend the use of rhodiola rosea for sports enthusiasts to support physical performance. Keywords: Rhodiola Rosea, Muscle Pain, Range of Motion, Exercise-Induced Muscle Damage, Inflammation, Healthy lifestyle

A prospective, randomised, controlled, double blinded, cross-over study on the effect of a single session of pulsed electromagnetic field therapy on signs of hip osteoarthritis in dogs

BackgroundCanine coxofemoral joint osteoarthritis is a common, painful and debilitating condition. The objective of this study was to evaluate if any measurable changes in pain or lameness occurred in this patient group immediately after a single treatment with pulsed electromagnetic field therapy. Eight dogs with coxofemoral joint osteoarthritis presenting with signs of pain and lameness were prospectively recruited to this randomised, controlled, double blinded, cross-over study. Subjects attended the research facility on two occasions for one active and one placebo treatment with pulsed electromagnetic field therapy. The immediate effect of one pulsed electromagnetic field therapy treatment on pain and lameness was measured subjectively with the Helsinki Chronic Pain Index and Visual Analogue Scale and objectively using a pressure sensitive walkway.ResultsA statistically significant difference (P = 0.03) for change in stride length in the affected limb was recorded for subjects between the active and placebo treatments with pulsed electromagnetic field therapy. Within the active treatment results, there was a statistically significant change in the measurement for reach (P = 0.04) and stride length (P = 0.047) which got shorter in the affected limb post treatment. For the subjective outcome measures, there was no statistically significant difference between the active and placebo treatments for the evening of the treatment day or the next morning from pre-treatment values. Within the placebo treatment results a statistically significant change (improvement) was detected in Visual Analogue Score (P = 0.03) between pre-treatment and the next morning values.ConclusionsThe findings of this study do not show demonstrable improvement in owner assessed pain levels or temporospatial performance in dogs with coxofemoral joint osteoarthritis immediately after a single application of pulsed electromagnetic field therapy.

The role of glucagon-like peptide 1 in the postprandial effects of metformin in type 2 diabetes: a randomized crossover trial.

Although metformin is widely used for treatment of type 2 diabetes (T2D), its glucose-lowering mechanism remains unclear. Using the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) antagonist exendin(9-39)NH2, we tested the hypothesis that postprandial GLP-1-mediated effects contribute to the glucose-lowering potential of metformin in T2D. In a randomized, placebo-controlled, double-blind, crossover study, 15 individuals with T2D (median HbA1c 50 mmol/mol [6.7%], body mass index 30.1 kg/m2, age 71 years) underwent, in randomized order, 14 days of metformin and placebo treatment, respectively. Each treatment period was preceded by 14 days without any glucose-lowering medicine and concluded by two 4 h mixed meal tests performed in randomized order and separated by >24 h with either continuous intravenous exendin(9-39)NH2 or saline infusion. Compared to placebo, metformin treatment lowered fasting plasma glucose (mean of differences [MD] 1.4 mmol/L × min [95% CI 0.8-2.0]) as well as postprandial plasma glucose excursions during both saline infusion (MD 186 mmol/L × min [95% CI 64-307]) and exendin(9-39)NH2 infusion (MD 268 mmol/L × min [95% CI 108-427]). The metformin-induced improvement in postprandial glucose tolerance was unaffected by GLP-1R antagonization (MD 82 mmol/L × min [95% CI -6564-170]). Metformin treatment increased fasting plasma GLP-1 (MD 1.7 pmol/L × min [95% CI 0.39-2.9]) but did not affect postprandial GLP-1 responses (MD 820 pmol/L × min [95% CI -1750-111]). Using GLP-1R antagonization, we could not detect GLP-1-mediated postprandial glucose-lowering effect of metformin in individuals with T2D. We show that 2 weeks of metformin treatment increases fasting plasma GLP-1, which may contribute to metformin's beneficial effect on fasting plasma glucose in T2D. Trial registration: Clinicaltrials.gov NCT03246451.

The Effects of Nordic Hamstring Exercise on Performance and Injury in the Lower Extremities: An Umbrella Review.

Due to their potential positive outcomes, hamstring eccentric exercises are becoming increasingly popular in training regimens. Among the various exercises, the Nordic Hamstring Exercise (NHE) is the most common. Despite its popularity, there are still some doubts about its benefits and risks. So, the aim of this umbrella review was to summarize the effects of NHE on performance and injury prevention. Following the PRISMA guidelines, a comprehensive literature search was conducted across multiple e-databases, according to the P (injured and non-injured athletes or recreationally active or healthy individuals) I (NHE) C (no intervention, placebo, or other interventions) O (performance or injury) S (systematic reviews) model. The quality of the studies was accessed with the AMSTAR-2. From the 916 systematic reviews found, only 10 could be included. They encompassed 125 studies, enrolling 17,260 subjects. The results from the studies indicate that NHE interventions demonstrated positive effects on sprint performance, muscle activation, eccentric strength, and muscle architecture (fascicle length, muscle thickness, and pennation angle). Furthermore, NHE is effective in preventing hamstring injuries (up to 51%). In conclusion, NHE should be integrated in training (especially, in the warm-up phase) for both enhancing athletic performance and preventing hamstring injuries. For achieving more positive results, it is recommended that high-volume is followed by low-volume maintenance, targeting 48 reps/week.

Effect of benralizumab on inflammation in skin after intradermal allergen challenge in patients with moderate-to-severe atopic dermatitis

BackgroundAtopic dermatitis is a skin barrier dysfunction characterized by tissue eosinophilia. Objective: In patients with atopic dermatitis (AD) we evaluated the effect of eosinophil depletion with benralizumab on markers of inflammation in skin after intradermal allergen challenge. Methods20 patients with moderate to severe AD completed a randomized, double-blind, placebo-controlled parallel-group study comparing 3 doses q4wk 30 mg subcutaneous benralizumab (n=9) to placebo (n=11). Allergen and saline control intradermal challenges were conducted before and after treatment with skin biopsies collected 24 hours after challenge. Early (ECR) and late cutaneous responses (LAR) were measured by skin wheal size. Eosinophils and IL-5Rα -bearing cells including eosinophil progenitor cells (EoP), basophils and mast cells were measured in papillary dermis by immunofluorescence microscopy, and EoP, hemopoietic progenitor cells (HPC) and ILC2 were measured in blood by flow cytometry. Outcomes were compared between placebo and benralizumab treatment groups using Mann-Whitney U-test. ResultsBenralizumab reduced eosinophils in blood (p<0.0001), and allergen challenged skin as measured by H&E and EG2 (p<0.05). Benralizumab lowered levels of EoP, mast cells and basophil numbers in skin, as well as EoP, HPC and ILC2s in blood (all p<0.05). There was a trend for improvement in the ECR response (p=0.095), but no effect on the LCR. ConclusionIn patients with moderate to severe AD, benralizumab treatment significantly inhibited accumulation of eosinophils and other IL-5Rα expressing cells in the papillary dermis after intradermal allergen challenge. Targeting IL-5Rα positive cells did not modulate the size of the allergen-induced skin wheal. (ClincialTrials.gov number, NCT03563066).

Transcutaneous electrical nerve stimulation (TENS) for pain control in women with primary dysmenorrhoea.

Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological treatment that works by delivering electrical currents via electrodes attached to the skin at the site of pain. It can be an alternative to pharmacological treatments. The mechanism of action of TENS for pain relief is related to the inhibition of the transmission of painful stimuli, release of endogenous opioids, and reduced muscle ischaemia of the uterus. Although it has been used for primary dysmenorrhoea ((PD); period pain or menstrual cramps), evidence of the efficacy and safety of high-frequency TENS, low-frequency TENS, or other treatments for PD is limited. To evaluate the effectiveness and safety of transcutaneous electrical nerve stimulation (TENS) in comparison with placebo, no treatment, and other treatments for primary dysmenorrhoea (PD). We searched the Gynaecology and Fertility Group's Specialized Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, AMED, CINAHL, and the Korean and Chinese language databases up to 9 April 2024. We also searched for ongoing trials in trials registries and the reference lists of relevant studies for additional trials. Language restrictions were not applied. We included randomized controlled trials (RCTs) that included women (aged 12 to 49 years) with PD. Included trials compared low-frequency TENS or high-frequency TENS with other TENS, placebo, or other treatment. Four review authors screened the trials, extracted the data according to the protocol, assessed the risk of bias using RoB 2, and assessed the certainty of evidence for all review comparisons and primary outcomes (i.e. pain relief and adverse effects) using the GRADE approach. This review replaces the current review, published in 2009. We included 20 RCTs involving 585 randomized women with high-frequency TENS, low-frequency TENS, placebo or no treatment, or other treatment. We included five comparisons: high-frequency TENS versus placebo or no treatment, low-frequency TENS versus placebo or no treatment, high-frequency TENS versus low-frequency TENS, high-frequency TENS versus other treatments, and low-frequency TENS versus other treatments. High-frequency TENS versus placebo or no treatment High-frequency TENS may reduce pain compared with placebo or no treatment (mean difference (MD) -1.39, 95% confidence interval (CI) -2.51 to -0.28; 10 RCTs, 345 women; low-certainty evidence; I2 = 88%). Two out of three RCTs reported no adverse effects and hence we were unable to estimate the effect of high-frequency TENS on adverse effects. Low-frequency TENS versus placebo or no treatment Low-frequency TENS may reduce pain compared with placebo or no treatment (MD -2.04, 95% CI -2.95 to -1.14; 3 RCTs, 645 women; low-certainty evidence; I2 = 0%). No trials reported adverse effects for this comparison. High-frequency TENS versus low-frequency TENS It is uncertain whether high-frequency TENS had an effect on pain relief compared with low-frequency TENS (MD 0.89, 95% CI -0.19 to 1.96; 3 RCTs, 54 women; low-certainty evidence; I2 = 0%). One trial contributed data on adverse effects but no adverse events occurred. High-frequency TENS versus other treatments It is uncertain whether high-frequency TENS had an effect on pain relief compared to acupressure (MD -0.66, 95% CI -1.72 to 0.40; 1 RCT, 18 women; very low-certainty evidence), acetaminophen (paracetamol) (MD -0.98, 95% CI -3.30 to 1.34; 1 RCT, 20 women; very low-certainty evidence), and interferential current therapy (MD -0.03, 95% CI -1.04 to 0.98; 2 RCTs, 62 women; low-certainty evidence; I2 = 0%). The occurrence of adverse effects did not differ significantly between high-frequency TENS and NSAIDs (OR 12.06, 95% CI 0.26 to 570.62; 2 RCTs, 88 women; low-certainty evidence; I2 = 78%). Low-frequency TENS versus other treatments It is uncertain whether low-frequency TENS had an effect on pain relief compared with acetaminophen (MD -1.48, 95% CI -3.61 to 0.65; 1 RCT, 20 women; very low-certainty evidence). No trials reported adverse effects for this comparison. High-frequency TENS and low-frequency TENS may reduce pain compared with placebo or no treatment. We downgraded the certainty of the evidence because of the risk of bias. Future RCTs should focus more on secondary outcomes of this review (e.g. requirement for additional analgesics, limitation of daily activities, or health-related quality of life) and should be designed to ensure a low risk of bias.

Kinésithérapie effectivement basée sur le placebo : comment les recherches de ces deux champs s’alimentent

Beginning by exploring the historical links between physiotherapy and placebo, we examine how placebo research can help physiotherapy. Focusing on three original contributions, we look at how placebo treatments work and how placebo effects might be used in clinics by modulating contextual factors. The first study demonstrates that open placebos are non-inferior to deceptive placebos. The second examines the acceptability of placebo treatments and the third how physiotherapists use placebo effects in their daily work by manipulating contextual factors. We close by examining at the importance of placebo research in the design of relevant control groups in rehabilitation research. Taken together, these results reflect on the epistemological basis for determining the efficacy of physiotherapy, and motivate the practice of ethical physiotherapy rooted in an in-depth understanding of placebo effects and contextual factors.

Quercetin intervention reduced hepatic fat deposition in patients with nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled crossover clinical trial

BackgroundNonalcoholic fatty liver disease (NAFLD) has become a growing public health problem worldwide. However, there is still lack of effective treatment strategies except lifestyle intervention. ObjectivesTo evaluate whether quercetin improves intrahepatic lipid content in patients with NAFLD. MethodsIn this randomized, double-blind, placebo-controlled crossover trial, 41 patients with NAFLD were randomly assigned to receive the quercetin (500 mg) or placebo capsules for 12 wk, then switched interventions for another 12 wk after a 4-wk washout period. The primary outcome was intrahepatic lipid content evaluated by magnetic resonance imaging estimated proton density fat fraction. The secondary outcomes were liver function measurements, etc. Safety outcomes included blood routine. ResultsA total of 36 patients completed the trial. In intention-to-treat analyses, the quercetin intervention moderately decreased the intrahepatic lipid contents from 11.5% ± 6.4% to 9.6% ± 5.8%, compared with the placebo intervention (decreased by 0.1% ± 2.6%, P = 0.013 and adjusted P value is 0.028). Body weight and body mass index were mildly reduced by 1.5 ± 2.6 kg and 0.5 ± 0.9 kg/m2 after the quercetin intervention (P < 0.05 and both adjusted P values are 0.038), whereas the reductions were only 0.2 ± 1.8 kg and 0.1 ± 0.7 kg/m2 after the placebo intervention. The intrahepatic lipid content reductions were noticeably positively associated with the body weight losses after the quercetin and placebo interventions (r = 0.557 and 0.412, P < 0.001 and P = 0.007, respectively). Subgroup analyses found that the reduction of intrahepatic lipid contents in females (3.0% ± 3.7%) was about twice as large as that in males (1.4% ± 2.5%) with a trend of statistical significance (P = 0.113 and adjusted P value is 0.061). There were no significant differences in other secondary and safety outcomes. No adverse events associated with study intervention were found. ConclusionsTwelve weeks treatment of quercetin could reduce intrahepatic lipid contents in patients with NAFLD, possibly explained by a slightly larger body weight loss in the quercetin group. Trial RegistrationThe trial is registered at www.chictr.org.cn as ChiCTR2100047904.

The effect of ischemic preconditioning on repeated sprint cycling performance: a randomized crossover study.

Ischemic preconditioning (IPC) has been suggested to improve exercise performance by 1-8%. Prior research concerning its impact on short-duration exercises, such as sprints, has been limited and yielded conflicting results. The aim of this study, which included a non-occlusion-based placebo control, was to determine whether IPC improves repeated sprint performance in a manner that accounted for psychophysiological effects. Twenty-two healthy males participated in this study, which employed a randomized crossover design. Following the 10-min baseline period, participants received intervention under four different conditions: 1) no-intervention control (CON); 2) non-occlusion-based placebo control (SHAM); 3) remote IPC (RIPC); and 4) local IPC (LIPC). Participants then performed a standardized repeated sprint cycling (5×10s maximal cycling sprint, separated by a 40-s rest in each set). Repeated sprint performance, as indexed by average power output, peak power output, and total work, the improvement was observed in the RIPC and LIPC during the initial phase (set 1-3) when compared with CON (P<0.05). SHAM condition also showed an increase in peak power output in the set 1 (CON 9.97±1.05 vs. SHAM 10.30±1.13 w/kg, P<0.05), which may represent a psychophysiological component in the IPC-induced improvement. Higher lactate concertation was found in the SHAM and LIPC groups, than in the CON group, 5 minutes after the exercise (CON 15.72±0.68 vs. SHAM 16.82±0.41 vs. LIPC 17.19±0.39 mmol/L, P<0.0001 for both, respectively). In conclusion, LIPC enhanced repeated sprint cycling performance during the initial phase, beyond what could be accounted for entirely by a psychophysiological effect. The improvement associated with RIPC, however, did not surpass the effect of a placebo intervention.

Placebo treatment affects brain systems related to affective and cognitive processes, but not nociceptive pain

Drug treatments for pain often do not outperform placebo, and a better understanding of placebo mechanisms is needed to improve treatment development and clinical practice. In a large-scale fMRI study (N = 392) with pre-registered analyses, we tested whether placebo analgesic treatment modulates nociceptive processes, and whether its effects generalize from conditioned to unconditioned pain modalities. Placebo treatment caused robust analgesia in conditioned thermal pain that generalized to unconditioned mechanical pain. However, placebo did not decrease pain-related fMRI activity in brain measures linked to nociceptive pain, including the Neurologic Pain Signature (NPS) and spinothalamic pathway regions, with strong support for null effects in Bayes Factor analyses. In addition, surprisingly, placebo increased activity in some spinothalamic regions for unconditioned mechanical pain. In contrast, placebo reduced activity in a neuromarker associated with higher-level contributions to pain, the Stimulus Intensity Independent Pain Signature (SIIPS), and affected activity in brain regions related to motivation and value, in both pain modalities. Individual differences in behavioral analgesia were correlated with neural changes in both modalities. Our results indicate that cognitive and affective processes primarily drive placebo analgesia, and show the potential of neuromarkers for separating treatment influences on nociception from influences on evaluative processes.

Preoperative Anxiolysis and Treatment Expectation (PATE Trial): open-label placebo treatment to reduce preoperative anxiety in female patients undergoing gynecological laparoscopic surgery - study protocol for a bicentric, prospective, randomized-controlled trial.

One of the most common concerns of patients undergoing surgery is preoperative anxiety, with a prevalence of up to 48%. The effects of preoperative anxiety continue beyond the preoperative period and are associated with more severe postoperative pain and poorer treatment outcomes. Treatment options for preoperative anxiety are often limited as sedatives cause side effects and their efficacy remains controversial. Placebo research has shown that optimization of positive treatment expectations, as can be achieved through placebo administration and education, has clinically relevant effects on preoperative anxiety, pain and treatment outcomes. As the administration of masked placebos raises ethical questions, clinical studies have increasingly focused on the use of open, non-deceptive placebo administration (open-label placebo, OLP). The use of OLPs to reduce preoperative anxiety and modify clinically relevant postoperative outcomes has not yet been investigated. This bicentric, prospective, randomized-controlled clinical trial (PATE Trial; German Registry for Clinical Studies DRKS00033221), an associated project of the Collaborative Research Center (CRC) 289 "Treatment Expectation", aims to alleviate preoperative anxiety by optimizing positive treatment expectations facilitated by OLP. Furthermore, this study examines a potential enhancement of these effects through aspects of observational learning, operationalized by a positive expectation-enhancing video. In addition, patient's perspective on the self-efficacy and appropriateness of OLPs prior to surgery will be assessed. To achieve these objectives, female patients will be randomized into three groups before undergoing gynecological laparoscopic surgery. One group receives the OLP with a positive rationale conveyed by a study physician. A second group receives the same intervention, OLP administration and rationale provided by a physician, and additionally watches a video on OLP presenting a satisfied patient. A third group receives standard treatment as usual (TAU). Outcome measures will be effects on preoperative anxiety and postoperative experience, particularly visceral and somatic postoperative pain. As the non-deceptive administration of placebos; when indicated; may yield positive outcomes without side effects, and as current treatment of preoperative anxiety is limited, evidence from clinical placebo research has the potential to improve outcomes and patient experience in the surgical setting.

Adolescents With a High Burden of New-Onset Mood Symptoms After Sport-Related Concussion Benefit From Prescribed Aerobic Exercise, a Secondary Analysis of 2 Randomized Controlled Trials.

Approximately 20% of students with sport-related concussion (SRC) report new symptoms of anxiety and depression which may be associated with delayed recovery and increased risk for developing a mood disorder. Early prescribed aerobic exercise facilitates recovery in athletes with concussion-related exercise intolerance. We studied the effect of aerobic exercise treatment on new mood symptoms early after SRC. Exploratory secondary analysis of 2 randomized controlled trials (RCT). Sports medicine clinics associated with UB (Buffalo, NY), CHOP (Philadelphia, PA), and Boston Children's Hospital (Boston, MA). Male and female adolescents (aged 13-18 years) diagnosed with SRC (2-10 days since injury). Participants were randomized to individualized targeted heart rate aerobic exercise (n = 102) or to a placebo intervention designed to mimic relative rest (n = 96). Incidence of Persisting Post-Concussive Symptoms (PPCS, symptoms ≥28 days). First RCT recruited from 2016 to 2018 and the second from 2018 to 2020. Of 198 adolescents, 156 (79%) reported a low burden (mean 1.2 ± 1.65/24) while 42 (21%) reported a high burden (mean 9.74 ± 3.70/24) of emotional symptoms before randomization. Intervention hazard ratio for developing PPCS for low burden was 0.767 (95% CI, 0.546-1.079; P = 0.128; β = 0.085) and for high burden was 0.290 (95% CI, 0.123-0.683; P = 0.005; β = 0.732). High burden of mood symptoms early after injury increases risk for PPCS, but the sports medicine model of providing early targeted aerobic exercise treatment reduces it. Nonsports medicine clinicians who treat patients with a high burden of new mood symptoms after concussion should consider prescribing aerobic exercise treatment to reduce the risk of PPCS and a mood disorder.

Impact of L-theanine and L-tyrosine on markers of stress and cognitive performance in response to a virtual reality based active shooter training drill

Ingestion of L-theanine and L-tyrosine has been shown to reduce salivary stress biomarkers and improve aspects of cognitive performance in response to stress. However, there have been no studies to concurrently examine the impact of both L-theanine and L-tyrosine ingestion during a mental stress challenge (MSC) involving a brief cognitive challenge and a virtual reality based active shooter training drill. Thus, the purpose of this study was to determine the impact of ingestion of L-theanine and L-tyrosine on markers of stress and cognitive performance in response to a virtual reality active shooter drill and cognitive challenge. The cognitive challenge involved a Stroop challenge and mental arithmetic. Eighty subjects (age = 21 ± 2.6 yrs; male = 46; female = 34) were randomly assigned L-tyrosine (n = 28; 2000 mg), L-theanine (n = 25; 200 mg), or placebo (n = 27) prior to MSC exposure. Saliva samples, state-anxiety inventory (SAI) scales, and heart rate (HR) were collected before and after exposure to the MSC. Saliva was analyzed for stress markers α-amylase (sAA) and secretory immunoglobulin A (SIgA). The MSC resulted in significant increases in sAA, SIgA, HR, and SAI. Ingestion of L-theanine and L-tyrosine did not impact markers of stress. However, the L-tyrosine treatment demonstrated significantly lower missed responses compared to the placebo treatment group during the Stroop challenge. These data demonstrate that ingestion of L-theanine or L-tyrosine does not impact markers of stress in response to a MSC but may impact cognitive performance. This study was pre-registered as a clinical trial ("Impact of supplements on stress markers”: NCT05592561).

Placebo immune-related adverse events (irAEs): A neglected phenomenon in cancer immunotherapy trials

PurposeThis study aims to investigate the underexplored prevalence of placebo-reported immune-related adverse events (irAEs) in immune checkpoint inhibitor (ICI) trials. MethodsWe searched public databases for randomized clinical trials (RCTs) involving ICI versus placebo treatments in patients with malignancies. Study characteristics and irAEs occurrences were extracted for meta-analyses using a random-effects model. Main OutcomesProportions of patients reported to experience any grade and grade 3 to 5 placebo irAEs; the risk ratio (RR) of reporting 'false' irAEs in the experiment arm (defined as 'false-irAE ratio', calculated by dividing the proportion of patients documented with irAEs in the placebo arm by that in the experimental arm). Results47 RCTs with 30,119 patients were analyzed. The pooled proportion of patients reported to experience any grade and grade 3 to 5 irAEs among placebo participants was 22.85 % (17.33 %−29.50 %) and 3.40 % (2.35 %−4.63 %), respectively. The pooled proportion of placebo-treated patients who experienced serious irAEs was 0.67 % (0.03 %−1.91 %). Treatment discontinuation and death due to placebo irAEs occurred in 0.69 % (<0.01 %−1.30 %) and 0.12 % (<0.01 %−0.40 %) of patients, respectively. The false-irAE ratio for any grade and grade 3 to 5 irAEs were 0.49 and 0.28. The false-irAE ratio was significantly higher in RCTs with control arms of placebo plus non-immunotherapy than in those with placebo alone (any grade: 0.57 vs. 0.32, P < 0.001; grade 3 to 5: 0.36 vs. 0.12, P = 0.009). ConclusionOur analyses of placebo-treated participants in ICI RCTs document the common occurrence of placebo irAEs. These findings are important for interpreting irAE profiles, avoiding inappropriate therapeutic interventions.

Exploring the Effect of Exercise versus Metformin on Insulin Resistance amongst Nigerians with Pre-diabetes: A Randomised Controlled Trial.

Pre-diabetes is an important risk factor for the development of type 2 diabetes and is common in Nigeria. Effective intervention can reverse the underlying pathogenesis of insulin resistance in pre-diabetes. This study aimed to determine and compare the impact of moderate exercise and metformin interventions on insulin resistance among participants with pre-diabetes. Using a randomised placebo-controlled design, 54 Nigerians with pre-diabetes were selected using simple random sampling. They were offered metformin, moderate exercise or placebo treatment and followed up for 12 weeks. Insulin resistance was assessed before and after the interventions and the outcome was compared. Forty-nine participants with pre-diabetes completed the study. Participants in both the exercise and metformin groups had significantly decreased insulin resistance compared to placebo after 12 weeks of intervention. However, there was a decrease in insulin resistance by 77.3% (homeostasis model assessment-insulin resistance [HOMA-IR]) and an increase in insulin sensitivity by 81.2% (quantitative insulin sensitivity check index [QUICKI]) in the exercise group. In comparison, participants in the metformin group had a decrease in insulin resistance by 66.3% (HOMA-IR) and an increase in insulin sensitivity by 76.2% (QUICKI). Amongst Nigerians with pre-diabetes, both moderate exercise and metformin have significantly higher efficacy than placebo in improving insulin resistance. However, moderate exercise improved insulin resistance more than the metformin intervention. Participants in this study need to be followed up for a longer period to assess the long-term effects of these interventions.

Long-term effects of fecal microbiota transplantation on gut microbiota after Helicobacter pylori eradication with bismuth quadruple therapy: A randomized controlled trial.

Eradicating Helicobacter pylori infection by bismuth quadruple therapy (BQT) is effective. However, the effect of BQT and subsequent fecal microbiota transplant (FMT) on the gut microbiota is less known. This prospective randomized controlled trial was conducted at a tertiary hospital in China from January 2019 to October 2020, with the primary endpoints the effect of BQT on the gut microbiota and the effect of FMT on the gut microbiota after bismuth quadruple therapy eradication therapy. A 14-day BQT with amoxicillin and clarithromycin was administered to H. pylori-positive subjects, and after eradication therapy, patients received a one-time FMT or placebo treatment. We then collected stool samples to assess the effects of 14-day BQT and FMT on the gut microbiota. 16 s rDNA and metagenomic sequencing were used to analyze the structure and function of intestinal flora. We also used Gastrointestinal Symptom Rating Scale (GSRS) to evaluate gastrointestinal symptom during treatment. A total of 30 patients were recruited and 15 were assigned to either FMT or placebo groups. After eradication therapy, alpha-diversity was decreased in both groups. At the phylum level, the abundance of Bacteroidetes and Firmicutes decreased, while Proteobacteria increased. At the genus level, the abundance of beneficial bacteria decreased, while pathogenic bacteria increased. Eradication therapy reduced some resistance genes abundance while increased the resistance genes abundance linked to Escherichia coli. While they all returned to baseline by Week 10. Besides, the difference was observed in Week 10 by the diarrhea score between two groups. Compared to Week 2, the GSRS total score and diarrhea score decreased in Week 3 only in FMT group. The balance of intestinal flora in patients can be considerably impacted by BQT in the short term, but it has reverted back to baseline by Week 10. FMT can alleviate gastrointestinal symptoms even if there was no evidence it promoted restoration of intestinal flora.

Long-term tafamidis efficacy in patients with transthyretin amyloid cardiomyopathy by baseline left ventricular ejection fraction.

Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) present with diverse left ventricular ejection fraction (LVEF). This study assessed tafamidis efficacy by baseline LVEF in the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and its long-term extension (LTE) study. Patients were randomized to 30 months of tafamidis or placebo treatment in ATTR-ACT. On completion, patients could join an LTE study to receive tafamidis. All-cause mortality (death, heart transplant, or cardiac mechanical assist device implantation) from baseline to the end of follow-up was assessed in patients continuously treated with tafamidis (80 mg meglumine or 61 mg free acid) or delayed tafamidis treatment (placebo in ATTR-ACT; tafamidis in the LTE study) according to baseline LVEF (<50% or ≥50%). Supportive outcomes were evaluated over a shorter follow-up. Patients with baseline LVEF <50% (n = 177: 88 tafamidis- and 89 placebo-treated) had signs of more severe heart failure, a higher proportion were Black, and had variant ATTR-CM than those with LVEF ≥50% (n = 171: 85 tafamidis- and 86 placebo-treated). At the end of follow-up (median 60-64 months), all-cause mortality was numerically higher in patients with baseline LVEF <50%; however, consistent with supportive findings, continuous tafamidis treatment was associated with a 47% reduction in mortality risk compared with delayed tafamidis treatment in patients with LVEF <50% and ≥50% (hazard ratio 0.53 [95% confidence interval 0.367-0.758]; p < 0.001, and 0.53 [0.344-0.818]; p < 0.01, respectively). Early initiation of tafamidis is associated with reduced mortality in patients with ATTR-CM, irrespective of initial LVEF value. ClinicalTrials.gov NCT01994889, NCT02791230.